Syk modulates EGFR signaling and functions in keratinocyte differentiation and squamous cell carcinoma progression

[Speaker] Yen-Yu Chang:1
[Co-author] Duen-Yi Huang:1, Wan-Wan Lin:1, Wei-Yu Chen:2, Chi-Long Chen:2
1:Department of Pharmacology, National Taiwan University, Taipei, Taiwan, 2:Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

Background: Syk is a non-receptor tyrosine kinase and has been implicated in the immunoreceptor signaling and adaptive immunity. Currently, Syk inhibitors are established for clinical trials in rheumatoid arthritis and lymphoma. Apart from its expressions in immune cells, the role of Syk in keratinocytes and solid tumors remains unclear.
Methods: We used primary human keratinocytes and A431 human epidermoid squamous cell carcinoma (SCC) as cell models, biochemical methods and confocal microscopy in this study.
Results: In this study, we found that Syk is activated by EGF in human keratinocytes and plays a negative role in terminal differentiation of keratinocytes. The protein level of Syk is downregulated along with the keratinocyte differentiation into corneocytes. Moreover, we found that Syk is a downstream signal molecule of EGFR in keratinocytes and involves in EGF-induced cell migration. Confocal microscopy indicated that Syk co-localizes with EGFR upon EGF stimulation, and Syk inhibition can impair the translocation of EGFR from the plasma membrane to the perinuclear site in
primary keratinocytes. In A431 human epidermoid squamous cell carcinoma (SCC) which displays EGFR overactivation, we also found the essential role of Syk to mediate EGFR-induced signaling pathways through Src family kinases.
Pharmacological inhibition of Syk can attenuate the EGF-induced phosphorylation of Akt, JNK, p38 MAPK, STAT1, STAT3 and EGFR in A431 cells. EGF can induce a Syk-dependent IL-8 gene and protein expression, while neither EGF nor Syk inhibitor R406 can affect the cell proliferation and viability. In A431 cells, EGF can induce EGFR translocation from cytosol to plasma membrane and perinuclear sites, and R406 can reduce the receptor trafficking to the plasma membrane. Moreover, we also observed the association of higher Syk activity to poorer overall survival of SCC
Conclusions: Taken together, Syk is an important signaling molecule downstream EGFR and plays important roles in keratinocyte functions and SCC development.
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